The overall goal of this research is to understand the mechanisms of maternal immune tolerance to the allogeneic fetus in pregnancy. The intimacy between the maternal immune system and the fetal allograft is an unparalleled physiological situation in which paternally inherited fetal antigens expressed by the fetus are unfailingly tolerated in normal pregnancy. The studies proposed herein further investigate previous observations that both murine and human pregnancy results in highly specific recognition of paternally- inherited fetal alloantigens. This holds true for both major and minor histocompatibility antigens. In this proposal, we will employ a murine model of a transgenic fetal minor histocompatibility antigen in combination with maternal CD4+ and CD8+ lymphocytes that specifically react to this antigen to investigate maternal lymphocyte responses and induction of tolerance to fetal antigen. We also investigate the expression, timing and presentation of fetal minor histocompatibility antigens in the human placenta. Our Specific Aims are: 1. Determine the phenotypic and functional properties of mHAg-specific T cells generated during murine pregnancy. 2. Determine the phenotypic and functional properties of antigen presenting cells displaying fetal antigen to T cells during pregnancy. 3. Investigate the expression and functional significance of fetally-derived mHAg in human pregnancy. Collectively, these studies will yield important new insights into the responses of maternal lymphocytes to fetal antigen that lead to immunological adaptation and harmonious coexistence of mother and fetus. This knowledge could in turn, give new light into the pathogenesis of pregnancy failure, and proved a basis for the development of therapeutic agents, not only co combat infertility, but also cancer, autoimmune disease and transplant rejection.